title: Aspirin use and risk of colorectal cancer according to BRAF mutation status.
abstract: OBJECTIVE
  Aspirin use reduces the risk of colorectal carcinoma. Experimental evidence implicates a role of RAF kinases in up-regulation of prostaglandin-endoperoxide synthase 2 (PTGS2, cyclooxygenase 2), suggesting that BRAF-mutant colonic cells might be less sensitive to the antitumor effects of aspirin than BRAF-wild-type neoplastic cells.
  
  
  OBJECTIVE
  To examine whether the association of aspirin intake with colorectal cancer risk differs according to status of tumor BRAF oncogene mutation.
  
  
  METHODS
  We collected biennial questionnaire data on aspirin use and followed up participants in the Nurses' Health Study (from 1980) and the Health Professionals Follow-up Study (from 1986) until July 1, 2006, for cancer incidence and until January 1, 2012, for cancer mortality. Duplication-method Cox proportional cause-specific hazards regression for competing risks data was used to compute hazard ratios (HRs) for colorectal carcinoma incidence according to BRAF mutation status.
  
  
  METHODS
  Incidence of colorectal cancer cases according to tumor BRAF mutation status.
  
  
  RESULTS
  Among 127,865 individuals, with 3,165,985 person-years of follow-up, we identified 1226 incident rectal and colon cancers with available molecular data. Compared with nonuse, regular aspirin use was associated with lower BRAF-wild-type cancer risk (multivariable HR, 0.73; 95% CI, 0.64 to 0.83; age-adjusted incidence rate difference [RD], -9.7; 95% CI, -12.6 to -6.7 per 100,000 person-years). This association was observed irrespective of status of tumor PTGS2 expression or PIK3CA or KRAS mutation. In contrast, regular aspirin use was not associated with a lower risk of BRAF-mutated cancer (multivariable HR, 1.03; 95% CI, 0.76 to 1.38; age-adjusted, incidence RD, 0.7; 95% CI, -0.3 to 1.7 per 100,000 person-years: P for heterogeneity = .037, between BRAF-wild-type vs BRAF-mutated cancer risks). Compared with no aspirin use, aspirin use of more than 14 tablets per week was associated with a lower risk of BRAF-wild-type cancer (multivariable HR, 0.43; 95% CI, 0.25 to 0.75; age-adjusted incidence RD, -19.8; 95% CI, -26.3 to -13.3 per 100,000 person-years). The relationship between the number of aspirin tablets per week and colorectal cancer risk differed significantly by BRAF mutation status (P for heterogeneity = .005).
  
  
  CONCLUSIONS
  Regular aspirin use was associated with lower risk of BRAF-wild-type colorectal cancer but not with BRAF-mutated cancer risk. These findings suggest that BRAF-mutant colon tumor cells may be less sensitive to the effect of aspirin. Given the modest absolute risk difference, further investigations are necessary to determine clinical implications of our findings.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Reiko
authors.initials: R
authors.lastname: Nishihara
authors.forename: Paul
authors.initials: P
authors.lastname: Lochhead
authors.forename: Aya
authors.initials: A
authors.lastname: Kuchiba
authors.forename: Seungyoun
authors.initials: S
authors.lastname: Jung
authors.forename: Mai
authors.initials: M
authors.lastname: Yamauchi
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Liao
authors.forename: Yu
authors.initials: Y
authors.lastname: Imamura
authors.forename: Zhi Rong
authors.initials: ZR
authors.lastname: Qian
authors.forename: Teppei
authors.initials: T
authors.lastname: Morikawa
authors.forename: Molin
authors.initials: M
authors.lastname: Wang
authors.forename: Donna
authors.initials: D
authors.lastname: Spiegelman
authors.forename: Eunyoung
authors.initials: E
authors.lastname: Cho
authors.forename: Edward
authors.initials: E
authors.lastname: Giovannucci
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Chan
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
mesh_terms: D000368:Aged; D001241:Aspirin / Q000008:administration & dosage* / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000517:prevention & control*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011448:Prostaglandin Antagonists / Q000008:administration & dosage* / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012306:Risk; D016019:Survival Analysis; D015854:Up-Regulation
chemical_list: D011448:Prostaglandin Antagonists; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D001241:Aspirin